Liu Johnson J, Galettis Peter, Farr Alistair, Maharaj Lenushka, Samarasinha Hasitha, McGechan Adam C, Baguley Bruce C, Bowen Richard J, Berners-Price Susan J, McKeage Mark J
Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland 1142, New Zealand.
J Inorg Biochem. 2008 Feb;102(2):303-10. doi: 10.1016/j.jinorgbio.2007.09.003. Epub 2007 Sep 26.
In this study we characterised the in vitro antitumour and hepatotoxicity profiles of a series of Au(I) and Ag(I) bidentate phenyl and pyridyl complexes in a panel of cisplatin-resistant human ovarian cancer cell-lines, and in isolated rat hepatocytes. The gold and silver compounds overcame cisplatin-resistance in the CH1-cisR, 41M-cisR and SKOV-3 cell-lines, and showed cytotoxic potencies strongly correlated with their lipophilicity. Complexes with phenyl or 2-pyridyl ligands had high antitumour and hepatotoxic potency and low selectivity between different cell-lines. Their cytotoxicity profiles were similar to classic mitochondrial poisons and an example of this type of compound was shown to accumulate preferentially in the mitochondria of cancer cells in a manner that depended upon the mitochondrial membrane potential. In contrast, complexes with 3- or 4-pyridyl ligands had low antitumour and hepatotoxic potency and cytotoxicity profiles similar to 2-deoxy-D-glucose. In addition, they showed high selectivity between different cell-lines that was not attributable to variation in uptake in different cell-types. The in vitro hepatotoxic potency of the series of gold and silver compounds varied by over 61-fold and was closely related to their lipophilicity and hepatocyte uptake. In conclusion, Au(I) and Ag(I) bidendate pyridyl phosphine complexes demonstrate activity against cisplatin-resistant human cancer cells and in vitro cytotoxicity that strongly depends upon their lipophilicity.
在本研究中，我们在一组顺铂耐药的人卵巢癌细胞系以及分离的大鼠肝细胞中，对一系列金（I）和银（I）双齿苯基及吡啶基配合物的体外抗肿瘤和肝毒性特征进行了表征。金和银化合物克服了CH1-cisR、41M-cisR和SKOV-3细胞系中的顺铂耐药性，并且显示出细胞毒性效力与其亲脂性密切相关。含有苯基或2-吡啶基配体的配合物具有高抗肿瘤和肝毒性效力，且在不同细胞系之间的选择性较低。它们的细胞毒性特征类似于经典的线粒体毒物，并且这类化合物的一个例子被证明以依赖线粒体膜电位的方式优先在癌细胞的线粒体中积累。相比之下，含有3-或4-吡啶基配体的配合物具有低抗肿瘤和肝毒性效力，其细胞毒性特征类似于2-脱氧-D-葡萄糖。此外，它们在不同细胞系之间显示出高选择性，这并非归因于不同细胞类型摄取的差异。该系列金和银化合物的体外肝毒性效力变化超过61倍，并且与它们的亲脂性和肝细胞摄取密切相关。总之，金（I）和银（I）双齿吡啶基膦配合物对顺铂耐药的人类癌细胞具有活性，其体外细胞毒性强烈依赖于它们的亲脂性。
